Letter | Published:

MicroRNA silencing for cancer therapy targeted to the tumour microenvironment

Nature volume 518, pages 107110 (05 February 2015) | Download Citation

Abstract

MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes1,2, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction3,4,5. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy6,7. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells8. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Gene expression data have been deposited in the Genome Expression Omnibus under accession number GSE61851.

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Acknowledgements

We thank M. Bosenberg, Y. Dang, A. Karabadzhak, and J. Zhou for discussions and suggestions; R. Ardito, M. Bonk, K. Card, D. Caruso, D. Jenci, D. Laliberte, W. Nazzaro, N. Santiago, and S. Wilson for rodent services; A. Brooks for tissue pathology services; Antech Diagnostics for complete blood count analysis; E. Aronesty, B. Cooper, and E. Norris at Expression Analysis for RNA-seq services; and J. Deacon, A. Kasinski, J. Sawyer, and C. Stahlhut for reading the manuscript. C.J.C. is the recipient of a Ruth L. Kirschstein Postdoctoral Fellowship from the National Cancer Institute/National Institutes of Health (NCI/NIH) (F32CA174247). Our work has been supported by grants from the NCI/NIH (R01CA131301), the National Heart, Lung, and Blood Institute (NHLBI)/NIH (R01HL085416), the National Institute of General Medical Sciences (NIGMS)/NIH (R01GM073857), the National Institute of Environmental Health Sciences (NIEHS)/NIH (R01ES005775), the NCI/NIH (R01CA148996), the National Institute of Biomedical Imaging and Bioengineering (NIBIB)/NIH (R01EB000487), the NHLBI/NIH (2T32HL007974), and pilot grants from the Yale Comprehensive Cancer Center.

Author information

Author notes

    • Christopher J. Cheng
    • , Imran A. Babar
    • , Zachary Pincus
    • , Francisco Barrera
    •  & Frank J. Slack

    Present addresses: Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, Connecticut 06410, USA (C.J.C.); OrbiMed Advisors LLC, 601 Lexington Avenue, 54th Floor, New York, New York 10022, USA (I.A.B.); Departments of Developmental Biology and Genetics, Washington University, St. Louis, Missouri 63110, USA (Z.P.); Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee–Knoxville, Knoxville, Tennessee 37996, USA (F.B.); Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA (F.J.S.).

Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA

    • Christopher J. Cheng
    • , Imran A. Babar
    • , Zachary Pincus
    • , Connie Liu
    •  & Frank J. Slack
  2. Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA

    • Christopher J. Cheng
    •  & W. Mark Saltzman
  3. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA

    • Christopher J. Cheng
    • , Francisco Barrera
    • , Alexander Svoronos
    •  & Donald M. Engelman
  4. Department of Therapeutic Radiology, Yale University, New Haven, Connecticut 06511, USA

    • Raman Bahal
    •  & Peter M. Glazer
  5. Department of Pathology, Yale University, New Haven, Connecticut 06511, USA

    • Demetrios T. Braddock

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Contributions

C.J.C., R.B., F.B., A.S., P.M.G., D.M.E., W.M.S., and F.J.S. designed the research; C.J.C. performed the research; R.B. synthesized the PNA; I.A.B. and C.J.C. developed and maintained the rodent colonies; C.J.C., Z.P., and C.L. performed the bioinformatics analysis; D.T.B. performed the pathological analysis; C.J.C., R.B., D.B., P.M.G., D.M.E., W.M.S., and F.J.S. analysed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Frank J. Slack.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Significantly differentially expressed genes upon withdrawal of miR-155 hyperexpression in miR-155-addicted tumors; genes are sorted by log2(fold change), with an FDR cutoff of 0.05.

  2. 2.

    Supplementary Table 2

    Identification of potential miR-155 targets. The first gene list includes miR-155 targets predicted using the miRWalk algorithm. The second list intersects the miRWalk targets with all genes that were upregulated upon miR-155 withdrawal; based on the hypergeometric distribution, the probability of achieving this observed overlap by chance is 3.7 x 10-9. The third list includes validated and predicted miR-155 targets compiled by SABiosciences. The remaining lists show the intersection of these sets with published sets of validated and putative miR-155 targets.

  3. 3.

    Supplementary Table 3

    Selection criteria for potential targets of miR-155 that are derepressed during miR-155 withdrawal-induced tumor regression.

Videos

  1. 1.

    Mouse with hind limb paresis before pHLIP-anti155 treatment

    Mouse with hind limb paresis before pHLIP-anti155 treatment.

  2. 2.

    Response of mouse in Supplementary Video 1 to pHLIP-anti155 treatment.

    Four days after initiating IV administration of pHLIP-anti155 (two injections of 2 mg/kg spaced 2 days apart), paresis in the mouse is alleviated.

  3. 3.

    Additional mouse with hind limb paresis before pHLIP-anti155 treatment.

    Additional mouse with hind limb paresis before pHLIP-anti155 treatment.

  4. 4.

    Response of mouse from Supplementary Video 3 to pHLIP-anti155 treatment

    Four days after initiating IV administration of pHLIP-anti155 (one injection of 2.5 mg/kg), the mouse from Supplementary Video 3 has improved posture and gait.

About this article

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DOI

https://doi.org/10.1038/nature13905

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